Millions of people today have Alzheimer's disease or some other form of dementia, such as frontotemporal dementia. Generally, definitive diagnostic testing is not possible since such involves testing of brain tissue. Other testing, which is also both costly and not practical, is not accurate and is done after symptoms of dementia have occurred and, thus the disease generally has already progressed significantly. This decreases the chance of effectively treating the disease since, at this time, no cure exists for dementia and treatments available are to slow the progression of the disease. Therefore, a need exists for a non-invasive method to predict or diagnose Alzheimer's disease and other dementias in a person prior to onset of the dementia so as to allow for earlier treatment to slow the onset or to lessen the effects of the disease. Additionally, a need exists for drug indicator tests that confirm mechanism of action of a drug and measure the extent of the effect of a given drug in treating Alzheimer's disease or other dementia with recipient patient specific efficacy.
Astrocytes or astroglial cells in the brain and spinal cord are distinguished by their star shape and prominent network of intermediate filaments, consist of numerous subsets, and are rich in glial fibrillary acidic protein (GFAP), glutamine synthetase (GluSyn) and vimentin. They are the most abundant central nervous system (CNS) glial cells with a frequency approximately five-times that of neurons and are functionally associated with neuronal synapses. Signals from several neural proteins, such as sonic hedgehog (SHH), may contribute to the diversity of astrocyte phenotypes. In addition, astrocytes may be activated to different functional states by various mediators, such as interferon-γ and cyclic guanosine-adenosine monophosphate (cGAMP). Astrocytes have many supportive neuronal functions including supplying nutrients, regulating extracellular ion concentrations, releasing neurotransmitters such as glutamate and adenosine triphosphate (ATP), inhibiting synaptic transmission by adenosine derived from ATP, and promoting the myelinating activity of oligodendrocytes through leukemia inhibitory factor released in response to ATP. Astrocytes also may facilitate repair of injuries to the CNS, in part by transformation into neurons, and appear to maintain some brain neural stem cells in a dormant state by secretion of several specific mediators.
Astrocytes accumulate at sites of deposition of Aβ peptides in the brain, where they internalize and degrade these peptides in an apparently protective process requiring expression of apolipoprotein E. At high intra-cellular and intra-nuclear levels, Aβ peptides modify many astrocyte activities ranging from mitochondrial functions to protein transcription. However, it has only recently been appreciated that some subsets of astrocytes also contain the amyloid precursor protein (APP), β-secretase, termed β-site APP cleaving enzyme 1 (BACE-1), and γ-secretase required for generation of Aβ peptides from APP, and that levels of these components in astrocytes are increased by fibrillary Aβ42 and several inflammatory cytokines. In the same studies, microglia contained none of these proteins of the Aβ peptide-generating pathway. Mechanisms of regulation of expression of BACE-1 involve several transcriptional elements, such as Sp1 and NFAT3, as well as post-transcriptional events. BACE-1 stability and function also are influenced by other neural proteins, including ubiquilin-1 and septin-8. A greater understanding of the relative role of these astrocyte pathways in generation of Aβ peptides in the brain has come from recent analyses of human induced pluripotent stem cell-derived neural cells. With these methods, astrocytes were shown to secrete high levels of Aβ peptides and astrocyte-like cells were prominently represented among the highest producers of Aβ peptides.